SUMMARY IgE-mediated food allergy is a common disease affecting approximately 1 in 13 children in the USA. For many, this is a lifelong disease with significant impairment in quality of life and no FDA-approved treatment. Although IgE is central to the pathophysiology of food allergy, the maintenance of IgE is poorly understood and is key to developing treatments that are truly disease modifying. We have shown that maintenance of IgE in mice requires IL-4 production from CD4+ T cells, and blocking IL-4/13 signaling in humans demonstrates that IgE requires continual Th2 cytokine production for maintenance. IgE memory in mice is contained within a population of antigen-specific IgG+ memory cells that continually renew the short-lived IgE+ plasma cell pool with T cell help. There is a lack of corresponding information on the cellular basis of IgE production in humans. We hypothesize that memory IgG+ B cells are the main B cell subset in humans from which allergen-specific IgE is derived under control of T cell help. We have identified significant heterogeneity in Th2 cytokine producing CD4+ T cells from food allergic individuals, including conventional Th2 cells, pathogenic effector Th2 cells (peTh2), and T follicular helper type-2 (Tfh2) cells. We propose that peTh2 cells are enriched in intestinal tissues where they can support class-switch to IgE from allergen-specific IgG memory B cells. We propose that Tfh2 cells are enriched in mucosal lymphoid tissues (tonsils) where they support class switch from nave and memory B cells, with the latter being the source of high-affinity IgE. Furthermore, we propose that CD27+ conventional Th2 cells are a reservoir of memory that maintain the pool of Tfh2 and peTh2 cells through local cues in the lymphoid tissues and mucosa, respectively. In this multi-PI proposal bringing together T cell and B cell expertise in food allergy, we will test these stated hypotheses using tonsil, gastrointestinal biopsies, and blood from patients with IgE- mediated food allergy. Understanding the maintenance and function of CD4+ Th2 subsets in the context of IgE- mediated food allergy will allow us to design disease modifying immunotherapies for the treatment of food allergy.